Pharmacologic Considerations of HCV Treatment
Transcript of Pharmacologic Considerations of HCV Treatment
Objectives Review pharmacokinetic properties of currently utilized
Hepatitis C medications Review drug interactions and drug elimination
considerations resulting from pharmacokinetic properties Discuss practical management of drug interactions and
drug elimination
Pharmacokinetics: Quick Review “Movement of drugs”
Study of the relationship between dose, amount of drug in the body and therapeutic or toxic effects of a drug
Pharmacokinetic data helps us understand: Dose and schedule Dose adjustments due to drug interactions and other
issues
Slide modified courtesy of Ryan Moss, PharmD
Pharmacokinetics: Quick Review
• Drug enters the blood
Absorption
• Drug travels in the blood
• Drug disbursement in the body
Distribution• Body changes the
drug• Usually in
intestine or liver
Metabolism
• Kidneys through urine
• Liver through stool
Excretion
Pharmacokinetics: Quick Review
CYP 3A4 Inhibitors Azole antifungals Protease inhibitors Ritonavir Calcium Channel Blockers
(CCBs) Clarithromycin Nefazodone Telithromycin
CYP3A4 Inducers Anticonvulsants Rifamycins St Johns Wort Non-Nucleoside Reverse
Transcriptase Inhibitors Modafinil Dexamethasone Bosentan Nafcillin
Pharmacokinetics: Final Review Drug Transporters Move drug across membranes Affect absorption, excretion, movement into organs Efflux ( ex. P-gp) Uptake ( ex. OATP)
P-gp Inhibitors: azoles, CCBs, PIs, amiodarone P-gp Inducers: carbamazepine, rifampin, phenytoin, St Johns
Wort P-gp Substrates: digoxin, loperamide OATP1B1 and BCRP substrate: rosuvastatin
Ledipasvir / Sofosbuvir
NS5A Inhibitor A: Acid increases absorption P-gp substrate
M: Oxidation/no CYP Inhibits P-gp & BCRP
E: Biliary elimination
NS5B polymerase inhibitor A: P-gp and BCRP substrate
M: Hydrolyzed to active molecule Does not inhibit or induce any
enzymes E: Renal clearance of active
metabolite
Ledipasvir/Sofosbuvir Avoid P-gp Inducers Anticonvulsants Rifamycins St Johns Wort
Acid suppressing agents Antacids: 4 hours before/after H2 blockers: take with or 12 hour separation; do not exceed equivalent of famotidine
40mg BID PPIs: take simultaneously while fasting; do not exceed omeprazole 20mg
Avoid HIV protease inhibitors and tenofovir DF co-administration Avoid in severe renal impairment (<30mL/min/1.73m2) Avoid amiodarone Avoid rosuvastatin
Velpatasvir / Sofosbuvir
NS5B polymerase inhibitor A: P-gp and BCRP substrate
M: Hydrolyzed to active
molecule Does not inhibit or induce
any enzymes E: Renal clearance of active
metabolite
NS5A inhibitor A: Acid increases absorption P-gp substrate
M: Metabolized Via CYP3A4,
2C8, and 2B6 Does not inhibit or induce and
enzymes E: Biliary elimination
Velpatasvir/Sofosbuvir Avoid P-gp Inducers Anticonvulsants Rifamycins St Johns Wort
Acid Suppressing medications Antacids: separate by 4 hours H2 blockers: take with or 12 hour separation; do not exceed equivalent of famotidine 40mg BID PPIs: take 4 hours after VEL; do not exceed omeprazole 20mg
CYP3A4 inhibitors/inducers Avoid HIV protease inhibitor and tenofovir DF co-administration Contraindicated with etravirine, efavirenz, nevirapine
Avoid in severe renal impairment (<30mL/min/1.73m2) Contraindicated with amiodarone Rosuvastatin: 10mg max dose
Velpatasvir /Sofosbuvir/ Voxilaprevir
NS3/4A Protease Inhibitor A: P-gp and BCRP substrate Food increases absorptionM: CYP3A4 substrateE: Biliary elimination
Velpatasvir/Sofosbuvir/Voxilaprevir Take with food Avoid in severe renal impairment (<30mL/min/1.73m2) Contraindicated with amiodarone Monitor digoxin levels Avoid P-gp Inducers
Anticonvulsants Rifamycins St Johns Wort
CYP 3A4 Inducers/inhibitors Contraindicated with atazanavir, lopinavir, tipranavir, and efavirenz Acid Suppressing medications
Antacids: separate by 4 hours H2 blockers: take with or 12 hour separation; do not exceed equivalent of famotidine 40mg BID PPIs: simultaneously with SOF/VEL/VOX on a fasting stomach; do not exceed omeprazole 20mg
Statins Pravastatin max dose 40mg Rosuvastatin, pitavastatin not recommended Monitor all others and use lowest recommended dose
Daclatasvir + Sofosbuvir
NS5A replication complex inhibitor A: P-gp substrate
M: Primarily metabolized by
CYP3A4 Inhibits CYP3A4
E: Biliary elimination
NS5B polymerase inhibitor A: P-gp and BCRP substrate
M: Hydrolyzed to active molecule Does not inhibit or induce any
enzymes E: Renal clearance of active
metabolite
Daclatasvir + Sofosbuvir CYP3A4 inducers Strong: Avoid Moderate: Increase dose to 90mg
Strong CYP3A4 inhibitors: reduce daclatasvir dose to 30mg* Avoid P-gp Inducers Anticonvulsants Rifamycins St Johns Wort
Avoid in severe renal impairment (<30mL/min/1.73m2) Avoid amiodarone
http://www.drugdevelopment-technology.com/projects/daklinza-daclatasvir-for-the-treatment-of-chronic-hepatitis-c-genotype-3-infection/
Glecaprevir/Pibrentasvir
http://chicago.suntimes.com/news/abbvie-pill-combo-gets-fda-ok-for-all-forms-of-hepatitis-c/
Glecaprevir + Pibrentasvir NS3/4A Protease Inhibitor A: P-gp, BCRP substrate OATP 1B1/3 substrate Increased by food
M: Secondary metabolism, mild
CYP3A4 Inhibits p-gp, OATP 1B1/3, BCRP Weak inhibitor of CYP 3A4, 1A2
and UGT1A1 E: Biliary elimination
NS5A replication complex inhibitor A: P-gp, BCRP substrate
M: No metabolism Inhibits p-gp, OATP 1B1/3, BCRP Weak inhibitor of CYP 3A4, 1A2 and
UGT1A1 E: Biliary elimination
Glecaprevir/Pibrentasvir Take with food No dose modification for renal impairment Not recommended in decompensated cirrhosis Avoid P-gp Inducers
Anticonvulsants Rifamycins St Johns Wort
HIV ART: Atazanavir contraindicated Not recommended: darunavir, lopinavir, ritonavir, efavirenz
Statins: Not recommended: atorvastatin, lovastatin, simvastatin Pravastatin: decrease by 50% Rosuvastatin: max dose 10mg
Decrease doses of digoxin Not recommended with ethinyl estradiol (increased ALT) Not recommended with cyclosporine >100mg daily
OmbitasvirParitaprevir/Ritonavir + Dasabuvir
https://www.hepmag.com/article/abbvies-viekira-pak-works-just-hepatitis-c-drug-resistancehttps://www.hepmag.com/article/fda-approves-oncedaily-hepatitis-c-regimen-viekira-xr
Ombitasvir / Paritaprevir / Ritonavir
NS3 protease inhibitor A: P-gp substrate Inhibits P-gp,
OATP1B1/3, BCRP M: Metabolized via CYP3A4
and to a lesser extent by CYP3A5
Inhibits CYP2C8, UGT1A1
E: Metabolism
NS5A inhibitor A: P-gp substrate
M: Metabolized via
hydrolysis then oxidative metabolism
Inhibits CYP2C8, UGT1A1
E: Biliary elimination
Pharmacokinetic enhancer A:
P-gp substrate M:
Metabolized by CYP3A4 Strong CYP3A4 inhibitor
E: Metabolism
Dasabuvir Nonnucleoside NS5B polymerase inhibitor A: Fat increases absorption P-gp substrate Inhibits BCRP
M: Metabolism via CYP2C8, and to a lesser extent by CYP3A Inhibits UGT1A1
E: Metabolism
Ombitasvir/Paritaprevir/ritonavir + Dasabuvir (PrOD) Take with food Avoid potent CYP3A4 inducers Avoid potent CYP3A4 inhibitors Avoid Ethiynl estradiol contraceptives HMG-CoA Reductase Inhibitors Avoid atorvasatin, simvastatin, and lovastatin Rosuvastatin: max dose 10mg
Contraindicated HIV medications: Elvitegravir/cobicistat/tenofovir alafenamide or tenofovir disoproxil fumarate Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz, etravirine, nevirapine Most HIV protease inhibitors
Quetiapine Apixaban Contraindicated with moderate to severe hepatic impairment (Child-Pugh B or C)
Elbasvir / Grazoprevir
NS5A inhibitor A: Fat increases absorption P-gp substrate Inhibits P-gp and BCRP
M: Metabolized via CYP3A4
E: Metabolism
NS3 inhibitor A: Fat increases absorption P-gp substrate Inhibits UGT1A1 and BCRP
M: Metabolism via CYP3A4 Inhibits CYP3A4
E: Metabolism
Elbasvir/Grazoprevir Avoid P-gp inducers Avoid CYP3A4 inducers Avoid strong CYP3A4 inhibitors Contraindicated HIV medications All HIV protease inhibitors Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz,
etravirine, nevirapine Contraindicated with moderate to severe hepatic impairment
(Child-Pugh B or C) Rosuvastatin: do not exceed 10mg
Simeprevir NS3 protease inhibitor A: Food improves absorption P-gp and OATP1B1 inhibitor
M: Metabolized by CYP 3A4 Inhibits CYP3A4 (intestinal)
E: Metabolism
Simeprevir Avoid in severe hepatic impairment/decompensated cirrhosis Avoid strong CYP3A4 inhibitors Avoid strong CYP3A4 inducers Contraindicated HIV medications All HIV protease inhibitors Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz,
etravirine, nevirapine Rosuvastatin: max dose 10mg
Ribavirin Purine nucleoside analogue A: Food improves absorption M: Minimal metabolism E: Renal elimination- dose adjust
Pregnancy category X
Summary/Conclusion Due to pharmacokinetic properties of HCV meds, drug
interactions are common Patients should be screened closely prior to and during
treatment for interactions Complicated patients (i.e. HIV co-infected, cirrhotic
patients, severe renal impairment) require additional considerations
Case 1: Steven Steven is a 24 year old white male referred to your clinic for HCV
evaluation after a recent hospitalization for endocarditis due to IV drug use. He currently takes zolpidem 5mg each evening for sleep, Adderall 5mg daily, and Lisinopril 5mg daily. He also reports occasional use of Tums after a spicy meal. Since his hospitalization, Steven completed rehabilitation and reports that he has not used IV drugs in 6 weeks. He has not received HCV treatment in the past and is eager to be treated. Work up reveals the following:
HCV RNA 1,004,879 IU/mL HCV GT2 Abdominal ultrasound with transient elastography reveals F1-
F2 fibrosis
Case 1: Steven What treatment strategy do you recommend at this time?
A. VEL/SOF x 12 weeksB. LDV/SOF x 8 weeksC. LDV/SOF x 12 weeksD. VEL/SOF x 8 weeksE. Delaying treatment until you can confirm drug
abstinence for >6 months
Case 1: Steven continued Steven is approved for the correct treatment listed above.
What counseling regarding his current medications would you provide?
VEL/SOF, VEL/SOF/VOX, LDV/SOF H2 Antagonist: simultaneously or 12 hours apart at a
maximum equivalent to famotidine 40mg twice daily Antacids: separate by 4 hours
Proton pump inhibitors: LDV/SOF: administer simultaneously under fasted
conditions at a maximum equivalent to pantoprazole 40mg VEL/SOF: administer VEL/SOF 4 hours before omeprazole
20mg with food. No other PPIs have been studied. 26% reduction in AUC of VEL/SOF
VEL/SOF/VOX: administer simultaneously under fasted conditions at a maximum equivalent to omeprazole 20mg
Acid Suppressing Agents and DAAs
Case 2: Patricia Patricia is a 38 y/o female referred for HCV evaluation and
treatment, who was diagnosed at time of HIV diagnosis in 2005. Her PMH includes HIV (last CD4 950 with HIV viral load
<20), bipolar disorder, and prior IVDU. Workup reveals: HCV RNA VL 12,500,000 GT 1a Elastography consistent with F1-F2 fibrosis Meds: (tenofovir DF/emtricitabine) + darunavir/ritonavir,
oxcarbazepine, quetiapine
Slide adapted from Cody Chastain, MD
Case 2: Which medication are concerning for potential drug-drug interactions with DAAs?
A. Tenofovir DFB. DarunavirC. RitonavirD. OxcarbazepineE. Quetiapine
HCV Medication Interactions
Acid-reducing agents Anticonvulsants Amiodarone, digoxin Azole antifungals Statins
AASLD/IDSA Guidelines
Questions?Autumn Zuckerman, PharmD, BCPS, AAHIVP
Acknowledgements: Ryan Moss, PharmD, AAVHIP